Adaption to chronic opiate exposure leads to tremendous health and social problems for addicts and pain patients, and thus imposes great costs for society in general. Despite years of intensive research directed toward understanding opiate tolerance and dependence, mechanisms of these changes remain unclear. Orphanin FQ is the recently identified endogenous ligand for the orphan opioid receptor (OFQ-R). OFQ-R was discovered by virtue of its high sequence homology to the family of opiate receptors, and OFQ also was found to be structurally related to members of the opioid family. Perhaps surprisingly, given these and other similarities (e.g., negative coupling to adenylate cyclase and overlapping central nervous system distribution), OFQ, acting at its receptor, appears to function as an endogenous antiopioid. Recent evidence suggests that changes in activity of this peptide may underlie processes associated with the neuroadaptation that ensues from chronic exposure to opiates. Most notably, OFQ administration blocks both opioid-mediated stress-induced analgesia and morphine analgesia, and there is an upregulation in both OFQ peptide and its receptor following repeated morphine administration. Furthermore, the development of opiate tolerance is reduced in transgenic mice that lack the OFQ-R (Ueda et al., 1997). The following studies are proposed to investigate the effect of OFQ on changes resulting from chronic exposure to opiates. Because coadministration of OFQ with morphine will block morphine effects without affecting morphine receptor occupancy, we propose to test whether such coadministration will alter the development of morphine tolerance, withdrawal, and place preference. Information from these studies will help determine whether morphine-receptor interactions are sufficient for such changes and thus help to answer the question of whether neuroadaption following chronic exposure to opiates results from cellular or systemic phenomena. Clinical applications of this work might include the development of novel treatment strategies and pharmacotherapies for opiate addicts and pain sufferers.